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Current Research and Scholarly Interests

I conduct clinical studies into the cases of children with RSV bronchiolitis. In addition, I collaborate with Dr. Dale Umetsu in the evaluation of alveolar macrophage behavior and presentation of antigen.

Abstract

Introduction of a rapid response team (RRT) has been shown to decrease mortality and cardiopulmonary arrests outside of the intensive care unit (ICU) in adult inpatients. No published studies to date show significant reductions in mortality or cardiopulmonary arrests in pediatric inpatients.To determine the effect on hospital-wide mortality rates and code rates outside of the ICU setting after RRT implementation at an academic children's hospital.A cohort study design with historical controls at a 264-bed, free-standing, quaternary care academic children's hospital. Pediatric inpatients who spent at least 1 day on a medical or surgical ward between January 1, 2001, and March 31, 2007, were included. A total of 22,037 patient admissions and 102,537 patient-days were evaluated preintervention (before September 1, 2005), and 7257 patient admissions and 34,420 patient-days were evaluated postintervention (on or after September 1, 2005).The RRT included a pediatric ICU-trained fellow or attending physician, ICU nurse, ICU respiratory therapist, and nursing supervisor. This team was activated using standard criteria and was available at all times to assess, treat, and triage decompensating pediatric inpatients.Hospital-wide mortality rates and code (respiratory and cardiopulmonary arrests) rates outside of the ICU setting. All outcomes were adjusted for case mix index values.After RRT implementation, the mean monthly mortality rate decreased by 18% (1.01 to 0.83 deaths per 100 discharges; 95% confidence interval [CI], 5%-30%; P = .007), the mean monthly code rate per 1000 admissions decreased by 71.7% (2.45 to 0.69 codes per 1000 admissions), and the mean monthly code rate per 1000 patient-days decreased by 71.2% (0.52 to 0.15 codes per 1000 patient-days). The estimated code rate per 1000 admissions for the postintervention group was 0.29 times that for the preintervention group (95% likelihood ratio CI, 0.10-0.65; P = .008), and the estimated code rate per 1000 patient-days for the postintervention group was 0.28 times that for the preintervention group (95% likelihood ratio CI, 0.10-0.64; P = .007).Implementation of an RRT was associated with a statistically significant reduction in hospital-wide mortality rate and code rate outside of the pediatric ICU setting.

Abstract

In 3 cases of severe multiple organ failure due to hemophagocytic lymphohistiocytosis (HLH) in children, the authors demonstrate the utility of continuous hemofiltration in attenuating the consequences of excess cytokine activity, with therapy titrated to the degree of lactic acidosis. HLH was diagnosed in 3 encephalopathic children with multiple organ failure, elevated ferritin (49,396-237,582 pmol/L; or 21,983-105,733 ng/mL), elevated serum triglyceride, and depressed cell lines. One had a known malignancy, one had EBV-associated lymphoproliferative disease, and one was previously healthy. Continuous hemofiltration was initiated, with the ultrafiltrate production rate and countercurrent dialysate flow titrated to metabolic acidosis as reflected by the serum lactate (maximum 3.5 mmol/L or 31.6 mg/dL). Hemofiltration was titrated upward until lactic acidosis resolved, through clearance of lactate or interruption of excess cytokine-driven activity; maximum prescription was 2000 mL/h ultrafiltrate production plus 2500 mL/h dialysate flow. Stability was achieved with hemofiltration, then substantial resolution occurred with treatment according to the HLH-94 protocol (dexamethasone, cyclosporin, VP-16, intrathecal methotrexate). One child succumbed to candidiasis. Another made a full recovery. A third succumbed to his primary malignancy. HLH should be suspected in unexplained or unresolving multiple organ failure. Titration of hemofiltration based on measurable parameters of cellular metabolism (e.g., lactate, base deficit) may stabilize the child with metabolic acidosis long enough to allow proper diagnosis and institution of definitive therapy. Hemofiltration is not a panacea but rather a stabilizing mechanism, with poorly understood effects on interstitial water and solute flux, that facilitates recovery over weeks, not days.

Abstract

Group A streptococcal (GAS) invasive disease has become increasingly common in recent years. However, acute bacterial meningitis caused by this pathogen is unusual. We report a case of GAS meningitis in a previously healthy 21/2-year-old child associated with a dramatically rapid course and fatal outcome. A literature review of previously reported cases is presented. This case serves as a reminder that GAS can cause severe meningitis in otherwise healthy hosts.

Abstract

Alveolar macrophages (AMCs) are the most abundant phagocytic cells in the lung, but they present antigen poorly to T cells.The objectives of our studies were to more clearly define the mechanisms by which AMCs present antigen to T cells and to determine whether AMCs actively inhibit T-cell activation.We studied purified human CD4 T cells and compared the capacity of allogeneic AMCs and peripheral blood monocytes to induce T-cell proliferation and cytokine production.We previously demonstrated that human AMCs fail to upregulate expression of B7-1 and B7-2 on stimulation with IFN-gamma. We now demonstrate that AMCs actively induce T-cell unresponsiveness (functional inactivation) in an antigen-specific manner and reduce the capacity of CD4 T cells to respond on secondary stimulation. The induction of unresponsiveness was reversed by the addition of CD28 costimulation or IL-2. However, interruption of Fas/Fas ligand interactions or of B7/CTLA-4 interactions did not prevent unresponsiveness, indicating that neither CTLA-4 triggering nor Fas-induced apoptosis was involved in the induction of T-cell unresponsiveness.These studies indicate that AMCs actively tolerize CD4 T cells in an antigen-specific fashion. We propose that AMCs mediate a form of immune privilege in the lungs that effectively limits immune responses in the pulmonary compartment but has little effect on systemic immunity.

Abstract

We experienced an unusual complication of life-threatening respiratory syncytial viral disease cardiovascular compromise. Life-threatening respiratory syncytial virus (RSV) infection has predominancy involved with ventilatory support for respiratory distress and/or failure. We performed a retrospective chart review of 20 consecutive infants admitted to the pediatric intensive care unit (PICU) for impending respiratory failure.Seventeen required ventilatory support. As part of the infants' initial assessment, blood pressure, distal perfusion [capillary refill time (CRT) > or = 3 sec], decreased peripheral pulses, and peripheral mottling were used to determine cardiovascular compromise. These infants received volume resuscitation either at the referring facility or the PICU until euvolemia was obtained, as determined by central venous pressure (CVP) monitoring (between 3 to 7 cm H20). Nine of the 20 infants did not respond to volume resuscitation alone and required vasopressor support in the form of: Dopamine (7 patients, 5-10 micrograms/kg/min), Dobutamine (2 patients, 5-7 micrograms/kg/min), and one who expired required both Epinephrine (600 ng/kg/min) and Dopamine (10 micrograms/kg/min). The mean ages of these 9 patients were 6.2 +/- 3.4 weeks (range 3-12 weeks), the mean duration of ventilation was 7.2 +/- 4.1 days (range 4-12 days). The mean duration of pharmacologic support was 69.7 +/- 47 hours (range 14-168 hours). The mean ages of RSV+ infants not requiring inotropic support was 19.4 +/- 27.4 weeks (range 1-90 weeks), and mean duration of ventilation was 5.5 +/- 5.9 days (range 2-20 days).The inotrope treated patients were weaned from pharmacologic support prior to extubation, without any hemodynamic deficits. Our experience with this rather high incidence of hemodynamic complications during this RSV epidemic was unexpected.These results substantiate the fact that younger patients with RSV disease are at both greater risk for pulmonary complications and cardiovascular deterioration and may thus benefit from pharmacologic support.

Abstract

To identify clinical variables of pneumonia in children with acute leukemia that predicted respiratory failure and mortality.A retrospective chart review of children with acute leukemia admitted to the hospital with the diagnosis of pneumonia or ARDS from March 1991 to April 1994.Lucile Salter Packard Children's Hospital at Stanford, a 168-bed teaching hospital and regional tertiary referral center for children in northern California.During this study period, 20% of the 174 admissions of children with acute leukemia had pneumonia at the time of admission or during the course of the hospitalization for a total of 36 admissions. The mean age of these children was 9.2 +/- 1.1 years.Eleven percent of the children with pulmonary infiltrates in one quadrant on the chest x-ray film at the onset of pneumonia and 53% of the children with pulmonary infiltrates in more than one quadrant at the onset of pneumonia died. Fifteen percent of the children without sepsis at the onset of pneumonia and 70% of the children with sepsis at onset died. Eighteen percent of the children without shock at the onset of pneumonia and 75% of the children with shock at the onset died. None of the children died who required < or = 3L/min of O2 to maintain SO2 > or = 95%, but 79% of the children who required > 3L/min O2 died. Using the criteria "> 3 L/min O2 by nasal cannula to maintain SO2 > or = 95%" to identify the nonsurvivors had a sensitivity of 100% and specificity of 88%. This specificity was not increased by combining the criteria "O2 requirements at any time" and "the extent of pulmonary infiltrates at the onset of pneumonia." All children who required mechanical ventilatory support for respiratory failure had previously received > 3 L/min O2 by nasal cannula to maintain SO2 > or = 95% for 37.8 +/- 12.9 h (range 3 to 96 h). Nine of the 10 children in our study who received mechanical ventilation died.In children with acute leukemia and pneumonia, the amount of O2 required to maintain SO2 > or = 95% may identify those who are likely to develop respiratory failure hours before mechanical ventilatory support is needed. The ability to identify children at risk for respiratory failure is not increased by combining the risk factors "oxygen requirements" and "extent of pulmonary infiltrates at the onset of pneumonia". Finally, only 10% of the children who required mechanical ventilatory support survived.

Abstract

Central venous catheter (CVC)-related thrombus formation has been increasingly recognized as a complication in adults and somewhat less frequently in children and neonates. However, the association of CVC thrombus and pulmonary embolism (PE) has rarely been reported in infants or children, and the few existing reports primarily involve chronic, indwelling CVCs such as Broviac or Hickman catheters. During an 18-month-period of autopsy review, we found that 5 of our pediatric intensive care unit patients had autopsy-proven CVC thrombus and pulmonary embolism. All of them had prolonged mechanical ventilation for respiratory failure and required insertion of one or more short-term, temporary CVCs during the course of routine critical care management. In retrospect, signs related to CVC thrombus were present in 4 patients (3 had positive blood cultures and 1 had persistent hypertension). PE was not diagnosed until autopsy in every case. The diagnosis may have been missed because the symptoms of PE are the same as those of severe lung disease. We, therefore, advocate a heightened suspicion of CVC thrombus formation and PE in critically ill children with respiratory failure and temporary CVCs and recommend early diagnostic ultrasound to confirm the diagnosis. Once a CVC thrombus is found, subsequent pulmonary deterioration may necessitate evaluation for acute PE.

Abstract

Sengers' syndrome is a rare condition consisting of congenital cataracts, mitochondrial myopathy, and hypertrophic cardiomyopathy. The syndrome is transmitted in an autosomal recessive pattern. Progressive cardiac failure is the cause of death in most patients. This report describes cardiac transplantation for the treatment of the cardiomyopathy associated with Sengers' syndrome.

Abstract

Alveolar macrophages, resident phagocytic cells in the lung that derive from peripheral blood monocytes, are paradoxically ineffective in presenting antigen to T cells. We found that antigen presentation by alveolar macrophages could be restored by the addition of anti-CD28 mAb to cultures of T cells and macrophages, indicating that costimulation by alveolar macrophages via the CD28 pathway was defective. In addition, we found that alveolar macrophages activated with IFN-gamma failed to express B7-1 or B7-2 antigens, which normally ligate CD28 on T cells and provide a costimulatory signal required for the activation of T cells. These observations are the first to demonstrate the inability of a "professional" antigen-presenting cell type to effectively express the costimulatory molecules B7-1 and B7-2. Inasmuch as immune reactions within the lung are inevitably associated with inflammatory injury to pulmonary tissue, these observations suggest that reduced expression of B7-1 and B7-2 by alveolar macrophages may be advantageous, as a critical mechanism involved in the induction of peripheral tolerance to the abundance of antigens to which mucosal tissues are continuously exposed.

Abstract

Chromosome band 11q23, the location of the HRX gene, is a site of recurrent translocations in human malignancies. Infants with acute lymphoblastic leukemia (ALL) commonly have 11q23 translocations and have an especially poor prognosis despite intensive chemotherapy. We analyzed 96 cases of infant ALL treated on three consecutive Pediatric Oncology Group protocols to determine the frequency and prognostic significance of molecular rearrangements of HRX. Overall, 78 cases (81%) had HRX rearrangements detected by Southern blot analysis performed with a single HRX cDNA probe, whereas 18 cases (19%) had germline HRX. Of the 78 cases with HRX rearrangements, only 50 had abnormalities of 11q23 detected cytogenetically. Molecular abnormalities of HRX were associated with early treatment failure and a very poor outcome. Estimated event-free survival for patients with HRX rearrangements was 19% (SE, 7%) at 3 years, compared with 46% (SE, 17%) for patients with germline HRX (P = .033 by the two-sided logrank test). Therefore, infants with ALL and molecular abnormalities of HRX represent a group with an extremely high rate of failure who clearly need innovative or experimental treatment. Furthermore, cytogenetic analysis alone failed to detected 36% of HRX rearrangements, suggesting that molecular analysis be performed on all infants with ALL to identify this group of high-risk patients.

Abstract

High-frequency jet ventilation (HFJV) was used in 29 children with severe ARDS complicated by pulmonary barotrauma (PBT). Treatment with HFJV was begun when PBT was progressing over a 24-h period while receiving conventional ventilation (CV). The mean (+/- SD) age was 0.95 +/- 1.21 years (range, 0.03-4 years). The most common diagnosis was viral pneumonia (n = 17); other diagnoses included aspiration pneumonitis (n = 4), bacterial pneumonia (n = 3), multiple trauma (n = 2), and near-drowning (n = 3). The Bunnell Life-Pulse ventilator was used at a rate of 240/min or 300/min, with inspiratory time of 0.02 sec. Twenty children survived (69%). Survivors and nonsurvivors had equal disease severity prior to HFJV as assessed by ventilator settings, alveolar-to-arterial oxygen tension gradient, oxygenation index, and blood gas values. Survivors had spent significantly less time on conventional ventilation prior to HFJV than nonsurvivors, with a mean (+/- SD) of 3.7 +/- 2.1 days vs 9.6 +/- 4.5 days, respectively (P < 0.05). Survivors underwent an average of 4.4 +/- 3.9 days of HFJV, which supported adequate gas exchange with lower airway pressures, and produced resolution or significant improvement in airleak on chest radiograph. In conclusion, we speculate that the application of HFJV early in the course of severe hypoxemic respiratory failure complicated by airleak, allows the reduction of airway pressures, thereby minimizing pulmonary barotrauma and allowing the lung to recover from the underlying insult. Further controlled evaluation of HFJV in this high risk group of patients is warranted.

Abstract

Although the antiviral agent ribavirin improves the course of lower respiratory tract disease in spontaneously breathing infants with respiratory syncytial virus infection, it is not known whether ribavirin can benefit infants with severe respiratory syncytial virus disease who require mechanical ventilation.We conducted a randomized, double-blind, placebo-controlled evaluation of ribavirin (20 mg per milliliter) administered continuously in aerosolized form to infants receiving mechanical ventilation for respiratory failure that was caused by documented respiratory syncytial virus infection.Of the 28 infants (mean [+/- SD] age, 1.4 +/- 1.7 months) enrolled, 7 had underlying diseases predisposing them to severe infection (mean age, 3.0 +/- 2.6 months), and 21 were previously normal (mean age, 0.8 +/- 0.9 month). Among the 14 infants who received ribavirin, the mean duration of mechanical ventilation was 4.9 days (as compared with 9.9 days among the 14 who received placebo; P = 0.01), and the mean length of supplemental oxygen use was 8.7 days (as compared with 13.5 days; P = 0.01). The mean length of the hospital stay was 13.3 days after treatment with ribavirin and 15.0 with placebo (P = 0.04). When only the 21 previously normal infants were considered, the mean length of the hospital stay was 9.0 days for the ribavirin recipients and 15.3 days for those who received placebo (P = 0.005).In infants who require mechanical ventilation because of severe respiratory syncytial virus infection, treatment with aerosolized ribavirin decreases the duration of mechanical ventilation, oxygen treatment, and the hospital stay.

Abstract

Naproxen, a nonsteroidal anti-inflammatory drug (NSAID), is a propionic acid derivative that possesses analgesic and antipyretic properties through inhibition of prostaglandin synthesis. The propionic acids have been considered the least toxic of the NSAIDs, and one, ibuprofen, is currently available as an over-the-counter medication. Though acidosis has been reported with ibuprofen, no such occurrence has been reported for naproxen sodium. We report the case of a 15-year-old girl who presented with severe metabolic acidosis and seizures that rapidly followed naproxen sodium ingestion. Serum bicarbonate levels returned to normal 12 hours after admission and correlated with the known pharmacokinetics of naproxen. The pharmacokinetics of naproxen and treatment of its overdose, and possible mechanisms of metabolic acidosis are reviewed.

Abstract

We examined two children with presumed shaken baby syndrome. Both children suffered severe, indirect closed head trauma with intracranial hemorrhage, sharply increased intracranial pressure, and extensive neurologic damage. In addition to extensive retinal and preretinal hemorrhages, bilateral symmetric white ring-shaped retinal folds were seen encircling the macula outside the vascular arcades. These retinal folds may be a hallmark of shaking injuries in child abuse victims.

Abstract

Seven children with immunocompromised states were referred to the pediatric bronchoscopy service for evaluation of pneumonia. Flexible fiberoptic bronchoscopy accompanied with bronchoalveolar lavage was performed in all seven of these children. A definitive diagnosis was made for six of these seven patients. The diagnosis included Pneumocystis carinii in three, Candida albicans in two, and cytomegalovirus in one. There were no complications associated with the procedure. Flexible fiberoptic bronchoscopy with bronchoalveolar lavage should be considered early in the evaluation of the immunocompromised child with pneumonia.

Abstract

Eight kittens were studied during high-frequency oscillatory ventilation (HFOV) using an airway vibrator. HFOV was performed at 1000 and 1800 cycle/min at three present oscillatory amplitude settings and with lungs normal and injured by saline lavage. Change in lung volume (LV) during HFOV was compared to change in LV obtained during static inflation at matched mean airway pressure (Paw) of 5, 10, 15 and 20 cm H2O. LV during HFOV was significantly higher than during static inflation, and increased as oscillatory amplitude increased. LV was significantly lower after lung injury for matched HFOV settings, and was not affected by rate. Dissociation of Paw and LV during HFOV is observed implying that mean alveolar pressure (Palv) exceeds Paw during HFOV in this experimental model. The safe clinical application of HFOV may involve measurement of Palv or LV.

Abstract

Fifteen infants with respiratory syncytial virus pulmonary infection admitted to our pediatric ICU from December 1, 1985 through April 30, 1986, required mechanical ventilation. These patients were placed on an open trial of ribavirin therapy. We describe a technique for the safe delivery of aerosolized ribavirin to these infants while on the ventilator. The agent was delivered for 16 h/day for 7 days. Modifications of the ventilator circuit were needed to prevent the condensation of the drug in the ventilator tubing and to allow for the safe and effective operation of the ventilator. A common ventilator strategy was used for all patients. The highest positive inspiratory pressure generated was 42 +/- 9.5 (SD) cm H2O, the highest PEEP was 5.9 +/- 3.2 cm H2O, the duration of ventilation was 10.7 +/- 8.5 days, and exposure to fraction of inspired oxygen was greater than or equal to 0.6 for 55.3 h. Ribavirin levels were measurable in two patients, thereby demonstrating that the drug was in fact delivered and absorbed. Our preliminary results demonstrate that ribavirin can be delivered to the patients with respiratory syncytial viral infections who require mechanical ventilation; however, further studies are indicated to evaluate the efficacy and dose responsiveness, alterations in pulmonary dynamics, and safety of ribavirin in delivery to infants requiring ventilation.

Abstract

Monitoring of the effectiveness of ventilation is a significant problem during high-frequency ventilation (HFV). The time necessary to achieve equilibrium of the arterial tension of carbon dioxide (Paco2) following step changes in ventilation is appreciable, because of large body stores of CO2. Waiting for Paco2 to reach equilibrium is not only time-consuming but a potentially dangerous means of monitoring ventilator adjustments during HFV. Five kittens of mean +/- SD 1,082 +/- 383 gm weight were studied during HFV, both with normal lungs and lungs injured by saline lavage-induced surfactant depletion. The transcutaneous tension of carbon dioxide (Ptcco2) was monitored continuously to determine the time required to achieve equilibrium of Paco2 following a step change in ventilation. The rate of pulmonary CO2 elimination (VECO2) was measured immediately before and immediately after (less than 12 sec) step changes in ventilation and was used to predict the change in Paco2 achieved once equilibrium was reestablished. With normal lungs, equilibration time following step changes in ventilation was found to be approximately 20 minutes. After step decreases in ventilation of the injured lung, achieving equilibrium state took significantly longer, approximately 30 minutes. The Paco2 predicted was significantly related to the change in Paco2 achieved at equilibrium for both normal and injured lung studies. We concluded that direct monitoring of VECO2 during HFV may be a useful clinical monitoring technique, allowing rapid and accurate assessment of the efficiency of ventilation following step changes in ventilation and potentially assisting in optimizing ventilator settings.

Abstract

The authors discuss the possible ways of managing the asphyxiated infant by considering the respiratory circumstances of the fetus and newborn. However, they conclude that further multicenter clinical trials are required to evaluate the efficacy of the various methods of management of delayed transition in cardiorespiratory function after birth.